NM_001141945.3:c.-24+733T>C

Variant names:

• chr10-88990206-A-G
• rs1800682
• NM_001141945.3:c.-24+733T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001141945.3(ACTA2):​c.-24+733T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,064 control chromosomes in the GnomAD database, including 22,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (22963 hom., cov: 32)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0250
• Publications: 351 publications found

Genes affected

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

FAS Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autoimmune lymphoproliferative syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet

ENSG00000286116 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-88990206-A-G is Benign according to our data. Variant chr10-88990206-A-G is described in ClinVar as Benign. ClinVar VariationId is 779595.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141945.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001141945.3		c.-24+733T>C		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+816T>C		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-182+816T>C		intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000415557.2	TSL:3	c.-24+733T>C		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-24+816T>C		intron	N/A	ENSP00000398239.2	P62736
	ACTA2	ENST00000713602.1		c.-182+816T>C		intron	N/A	ENSP00000518898.1	P62736

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81399 AN: 151942 Hom.: 22905 Cov.: 32

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.513

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81523 AN: 152064 Hom.: 22963 Cov.: 32 AF XY: 0.535 AC XY: 39759 AN XY: 74334

African (AFR) AF: 0.721 AC: 29904 AN: 41470

American (AMR) AF: 0.531 AC: 8119 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1425 AN: 3468

East Asian (EAS) AF: 0.472 AC: 2439 AN: 5166

South Asian (SAS) AF: 0.434 AC: 2092 AN: 4820

European-Finnish (FIN) AF: 0.450 AC: 4761 AN: 10580

Middle Eastern (MID) AF: 0.490 AC: 142 AN: 290

European-Non Finnish (NFE) AF: 0.458 AC: 31118 AN: 67964

Other (OTH) AF: 0.516 AC: 1087 AN: 2106

Alfa AF: 0.487 Hom.: 78067

Bravo AF: 0.550

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autoimmune lymphoproliferative syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.54
PhyloP100		-0.025
PromoterAI		0.062	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800682; hg19: chr10-90749963;